This invention relates to new quinuclidine derivatives and, in particular, to 3-amino-2-aryl quinuclidines. These compounds are substance P antagonists and are useful in the treatment of gastrointestinal disorders, inflammatory disorders, central nervous system disorders and pain.
U.S. Pat. No. 3,560,510 refers to certain 3-amino-2-benzhydrylquinuclidines as diuretic agents, and to the corresponding unsubstituted 3-benzylamino compounds as intermediates for preparing the same. E. J. Warawa et al., in Journal of Medicinal Chemistry, 18,587 (1975), refers to other members of the same series wherein the 3-amino moiety is either ethylamino, .beta.-phenylethylamino, .beta.-isopropylamino or 2-furfurylamino.
PCT Patent Application PCT/US 90/00116, assigned in common with the present application, refers to 3-amino piperidine derivatives and related compounds that are substance P antagonists useful in the treatment of inflammatory and central nervous system disorders.
PCT Patent Application PCT/US 88/04205, also assigned in common with the present invention, refers to cis-3-[(cyclic)methylamino]-2-[(.alpha.-substituted)arylmethyl]quinuclidin es, 3-[(cyclic)methylamine]-2-[(.alpha.-substituted)arylmethyl]quinuclidines a nd cis-3-[(cyclic)methyleneamino]-2-[(.alpha.-substituted)arylmethyl]quinucli dines that are substance P antagonists useful in the treatment of gastrointestinal disorders, central nervous system disorders,inflammatory diseases and pain.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals (having originally been isolated from gut) and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in U.S. Pat. No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has been shown to be involved in the transmission of pain (see B. E. B. Sandberg et al., Journal of Medicinal Chemistry, 25, 1009 (1982)), and more recently in the etiology of migraine and cluster headache (P. J. Gaddsby et al., Ann. Neurol., 23, 193 (1988)), as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, and in gastrointestinal disorders such as ulcerative colitis and Crohn's disease, etc. (see D. Regoli in "Trends in Cluster Headache," edited by F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, pp. 85-95, (1987)).
In the past, some attempts have been made to provide peptide-like substances that are antagonists for substance P and other tachykinin peptides in order to more effectively treat the various disorders and diseases listed above. The peptide-like nature of such substances make them too labile from a metabolic point of view to serve as practical therapeutic agents in the treatment of disease. The non-peptide antagonists of the present invention, on the other hand, do not possess this drawback.